Prefrontal rTMS modulates dynamic expectancy processes to shape subsequent pain experience

Pain expectancy is a major determinant of pain perception, and identifying effective approaches to modulate expectancy may provide new opportunities for pain intervention. High-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex (DLPFC) has been implicated in expectancy-related pain modulation. However, it remains unclear how DLPFC-rTMS influences distinct stages of expectancy processing and how these changes relate to subsequent pain experience. Thirty-three healthy participants completed a randomized, double-blind, sham-controlled crossover study. Participants received real or sham high-frequency DLPFC-rTMS and performed a pain expectancy paradigm before and after stimulation while EEG was recorded. The paradigm dissociated expectancy formation and maintenance under certain and uncertain predictive contexts. Behaviorally, DLPFC-rTMS reduced pain intensity and unpleasantness, accompanied by a reduction in expected pain, and mediation analysis identified an indirect effect through expected pain. At the neural level, DLPFC-rTMS increased contextual cue-evoked P2 responses relative to sham during expectancy formation but reduced anticipatory N1 and contingent negative variation (CNV) responses during expectancy maintenance. During pain experience, laser-evoked N1 responses showed a context-dependent pattern, with greater attenuation under uncertainty. Importantly, mediation analyses identified distinct stage-related indirect associations: stimulation-related changes in contextual P2 responses were linked to subsequent laser-evoked N1 responses, whereas changes in anticipatory CNV and anxiety were jointly associated with subsequent pain ratings. Together, these findings demonstrate that DLPFC-rTMS modulates dynamic expectancy processes across distinct stages of pain anticipation, with formation- and maintenance-related changes linked to different aspects of subsequent pain processing.